Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and it shares many common features, such as aberrant protein aggregation, with a broader spectrum of neurodegenerative diseases. Despite the knowledge that the loss of specific dopaminergic neurons in the midbrain is largely responsible for many of the clinical presentations of PD, there are significant unknowns about the mechanisms that lead to neuronal death. Genetic studies have identified new mutations and gene defects that can be responsible for disease. Although familial PD is relatively rare, these genetic findings have led to critical insights toward understanding the underlying cause of disease and they may begin to define important biological pathways involving the interaction of these gene products. The identification of mutations in the alpha-synuclein gene has revealed that this protein is the major component of disease-characteristic inclusions known as Lewy bodies. Furthermore, various types of alpha-synuclein filamentous inclusions have been shown to be involved in the etiology of many neurodegenerative diseases. However, there is evidence to suggest that the formation of these mature inclusions and/or the small oligomers, which can take the appearance of """"""""spheres"""""""", can be involved in degeneration. In this proposal, the novel (E46K) mutation in alpha-synuclein, previously identified mutants and the wild-type protein will be studied in vitro, in tissue culture paradigms and in transgenic mice to investigate the molecular interactions and mechansims that lead to the aberrant polymerization of alpha-synuclein. The role of small polymeric """"""""sphere"""""""" compared to mature filamentous inclusions in the disease process will be assessed. Defects in the DJ-1 gene have been linked to PD or PD-like disease, and an interactive pathogenic link between DJ-1 and alpha-synuclein, perhaps involving oxidative stress mechanisms, in normal and disease state will be evaluated. These findings should provide important information as to the directions for planning for effective therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG009215-20
Application #
7844839
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
20
Fiscal Year
2009
Total Cost
$285,183
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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